Autoimmune diseases such as systemic lupus erythematosus (SLE), myasthenia gravis (MG) and idiopathic thrombocytopenic purpura (ITP) occur when the immune system of an individual is triggered to recognize and attack self components. For example, SLE is a multisystemic autoimmune disease with a great diversity of clinical manifestations, ranging from mild clinical findings with typical abnormal laboratory tests, to a life-threatening condition. Laboratory abnormalities include high titers of autoantibodies to a vast array of tissue antigens. The most characteristic are those directed against components of the cell nucleus such as DNA, RNA, histones, nuclear proteins and protein-nucleic complexes. The clinical course of SLE is highly variable and unpredictable, frequently involving periods of remissions and relapses.
The survival of patients with SLE has improved remarkably over the past decades, mainly due to the use of corticosteroids and cytotoxic drugs. While such medications have powerful anti-inflammatory and immunomodulatory effects, their use is severely limited by immunosuppression, myelosuppression and/or numerous other frequent side effects. A safe and efficient mode of immunomodulatory therapy for this disorder is still lacking.
Intravenous immunoglobulin (IVIG) is a highly purified IgG preparation produced from pooled human plasma collected from thousands of healthy blood donors. It is known that IVIG can cause clinical improvement of patients suffering from autoimmune diseases. Administration of high dose intravenous immunoglobulin (IVIG) is immunoregulatory but not immunosuppressive or myelotoxic. IVIG is capable not only of modulating SLE in animal models and in humans but it also may provide a defense against infection rather than encouraging it. However, using IVIG in the treatment of SLE is at present limited by cost, a poor understanding of the mechanism of action and anecdotal reports presented in the literature regarding clinical efficacy.
Antibodies are classified into different classes based on the structure of their heavy chains. These include IgG, IgM, IgA and IgE. Antibodies having the same constant structure are considered as being of the same isotype. Antibodies of the same isotype having different antigenic determinants as a result of the inheritance of different alleles are called allotypes. Antigenic determinants in the variable regions of L and/or H chains that are associated with the antigen-binding site of an antibody are called idiotypes. Antibodies raised or which react against an idiotype are called anti-Idiotypic antibodies (anti-Id).
U.S. Pat. No. 4,690,905 (Diamond) discloses the preparation of monoclonal (mAB) anti-Id antibodies to human anti-DNA antibodies. The mABs bind a determinant present on anti-DNA antibodies of a plurality of SLE patients. The determinant is preferably outside the DNA binding site of the antibodies. Also disclosed are diagnostic reagents for the determination in serum of anti-native DNA antibodies, and therapeutic reagents which may be used in a method to remove anti-native DNA antibodies from the serum of patients suffering from SLE.
Shoenfeld Y, et al., (1983) J. Exp Med. 158(3):718-30 describes the evaluation of idiotypic cross-reactions in 60 polynucleotide-binding monoclonal lupus auto-antibodies produced by human-human hybridomas that were derived from seven unrelated patients with SLE. Three anti-idiotype reagents were prepared by immunization of rabbits or a mouse with monoclonal auto-antibodies from two patients. Binding of the three reagents to their corresponding idiotypes was inhibited by one or more polynucleotides, an indication that the anti-idiotypes reacted with the variable regions of the auto-antibodies. A monoclonal anti-idiotype reagent cross-reacted with autoantibodies from six of the seven patients, and was named 16/6. The idiotypic cross-reactions of immunoglobulins from unrelated patients suggest that the autoantibodies are derived from related families of germ line genes that are expressed by patients with SLE.
Evans, M. J. et al (1991) J. Clin. Immunol. 11:291-5 describes the preparation of anti-Id antibodies from pooled normal human IgG which bind to anti-DNA antibodies derived from sera of SLE patients. It is postulated that the therapeutic effect of IVIG on SLE patients may be due in part to the presence in IVIG of anti-Idiotype antibodies.
This hypothesis was further supported in a subsequent article by the same authors (Evans, M. and Abdou, N. I. (1993) Lupus 2:371-375) which describes the in vitro modulation of anti-DNA secreting peripheral blood mononuclear cells derived from lupus patients by anti-Id antibodies purified from IVIG.
Williams Jr., R. C., et al (1994) Clin. Immunol. Immunopath. 73:215-223 describes a number of idiotypic (Id) markers related to anti-DNA antibodies associated with SLE. These markers include 16/6, F4, 3I and 8.12. 43% of 100 cationic human IgG myeloma proteins isolated from patients with multiple myeloma were found to show the presence of at least one of the Id markers. It is stated that several of the anti-DNA Ids appear to be associated, but that the exact structural basis requires further study.
WO 96/30057 (Mazes) discloses synthetic peptides duplicating portions of the complementarity-determining region (CDR) of the heavy or light chains of a pathogenic anti-DNA Mab that induce SLE-like disease in mice (experimental SLE). Specifically, the sequences of 5 peptides of 12-30 amino acids are disclosed. Also disclosed is the use of such peptides for inhibiting the proliferative response of T-lymphocytes isolated from a SLE patient.
Waisman, A. et al (1997) Proc. Natl. Acad. Sci. 94:4620-4625 describes the synthesis and characterization of two peptides based on sequences of CDR1 and CDR3 of a pathogenic anti-DNA Mab that bears the 16/6 Id. The peptides were found to modulate experimental SLE in mice.
U.S. Pat. No. 6,231,856 (Williams) discloses a method for treating SLE by administrating an antibody composition comprising purified anti-Id antibodies that have specificity for idiotypic determinants located on anti-DNA antibodies (anti-DNA anti-Id). Also disclosed is a method for purifying anti-DNA anti-Id from IVIG In the method, anti-DNA myeloma antibodies from a patient with gamaglubonemia that express idiotypic determinants are bound to a solid phase. IVIG is passed through the solid phase, and the bound fraction is eluted, the bound fraction containing the anti-DNA anti-Id.
The Williams patent also discloses the possibility of preparing synthetic peptides capable of duplicating idiotypic determinants of self-reactive autoantibodies. Such determinants may be identified through a comparison of hydropathic profiles of idiotypic-anti-Idiotypic interaction based on a computer program, as is described in Maier, C. C. et al (1994) Immunomethods 5:107-113. These synthetic peptides maybe bound to a solid phase and used to purify anti-DNA anti-Id from IVIG, as described above.
Zhang, W. et al (2001) Scand. J. Immunol. 53:192-197 describes the isolation of human anti-Idiotypes from four SLE sera which were found to demonstrate broad cross reactivity to both polyclonal and monoclonal anti-DNA antibodies isolated from SLE patients. The anti-Idiotypes were isolated on a purified IgG anti-dsDNA F(ab′)2 affinity column prepared from a single lupus patient.
Monaci, P. et al (2001) Europ. J. of Biochem. 268:4758-4768 describes the screening and identification of ligands using five random peptide phage display libraries and serum antibodies from noninfected individuals and patients infected by hepatitis C virus (HCV). Multimeric synthetic peptides that mimic several immunodominant epitopes of the virus were used to develop a diagnostic assay which detects antibodies to HCV in serum.
Sun, Y. et al (2001) Int. Immunol. 13:223-232 describes the use of anti-dsDNA antibodies isolated from the sera of SLE patients to screen a phage peptide library for peptides which mimic antigenic and immunogenic epitopes on dsDNA as mimotopes. The synthetic peptide mimotope had the sequence RLTSSLRYNP (SEQ ID NO:1), and was recognized by 88% of anti-dsDNA antibody-positive SLE sera which cross react with ssDNA.